The effect of S-alkylation on organocatalytic enamine activation through imidazolidine-4-thiones

Imidazolidine-4-thiones have been suggested as potential prebiotic organocatalysts for light-driven α-alkylations of aldehydes by bromoacetonitrile. However, imidazolidine-4-thiones react with bromoacetonitrile to give S-cyanomethylated dihydroimidazoles. Kinetic studies show that enamines derived from these cyclic secondary amines and aldehydes are more nucleophilic than enamines derived from aldehydes and MacMillan organocatalysts.


General
Chemicals. Chemicals used in the synthesis were purchased from commercial sources (Acros Organics, Sigma-Aldrich, Alfa Aesar by Thermo Fischer Scientific, VWR International GmbH (Avantor), and TCI Europe) and used without purification unless otherwise indicated.
Tetrahydrofuran was dried using sodium metal and distilled prior to use. Commercially available acetonitrile (99% extra dry over molecular sieves, Acros Organics), toluene (≥99.7% pure, Sigma-Aldrich), or dichloromethane (HPLC grade, VWR) used in synthetic procedures were used without purification. Molecular sieves (4 Å) were heated to 350 °C under vacuum for 6 h and then stored in a desiccator. All reactions were performed using dried glassware (dried using a heat gun under vacuum) under an atmosphere of nitrogen or argon except when using aqueous reagents.
Reactions were monitored using thin layer chromatography with either silica gel 60 aluminum backed plates with F-254 fluorescence indicator or neutral aluminium oxide 60 aluminium backed plates with F-254 fluorescence indicator (both from Merck, Darmstadt). Pentane was distilled prior to use for column chromatography. Triethylamine was used without purification. Flash column chromatography was performed on either silica gel 60 (0.040-0.063 nm) purchased from Merck, Darmstadt, or neutral aluminium oxide from Sigma Aldrich.
Melting points were measured using a Büchi melting-point M-560 device and are not corrected. X-ray data was measured on a Bruker D8 Venture TXS system equipped with a multilayer mirror monochromator and a Mo Kα rotating anode X-ray tube (λ = 0.71073 Å).
Kinetics. The kinetics of the reactions of the enamines 4 and 5 with the electrophiles 7a-7g were followed by UV/Vis spectroscopy by using an Applied Photophysics SX.20 stopped-flow spectrophotometer (10 mm light path). A constant temperature (20.0 ± 0.2 °C) was maintained through the use of a circulating bath cryostat. All solutions were prepared under an atmosphere of argon or nitrogen with HPLC grade acetonitrile (VWR) flushed with nitrogen or freshly distilled dichloromethane. The kinetic stopped-flow measurements were initiated by mixing equal volumes of acetonitrile (or dichloromethane) solutions of the nucleophiles and electrophiles. Nucleophile concentrations were at least ten times higher than electrophile concentrations to achieve pseudo-first order kinetics.
A conventional UV/Vis spectroscopic work station (J&M TIDAS diode array spectrometer with Hellma quartz insertion probe, circulating bath cryostat) was used to follow the kinetics of the slow reaction of 4 with 7g at 20 °C in acetonitrile.
The first-order rate constants k obs (s -1 ) were obtained from the decay of the absorbance at or close to the absorption maximum of the coloured reference electrophiles by least squares fitting of the equation A t = A 0 exp(-k obs t) + C to the exponential absorption decay curve. Plots of k obs (s -1 ) versus the nucleophile concentration gave the second-order rate constants k 2 (M -1 s -1 ) as slopes of the linear correlations.

S7
The NMR resonances for 3 were assigned by comparison with the 1D and 2D NMR spectroscopic data of an independently prepared sample of 3 (see Section 3). The formation of 3 was also observed when 2,2,5,5-tetramethylimidazolidine-4-thione (1) was mixed with bromoacetonitrile and 2,6-lutidine in acetonitrile without the addition of propanal.
The enamine 4 was only detected when 2,2,5,5-tetramethylimidazolidine-4-thione (1) reacted with a mixture of propanal and bromoacetonitrile or when preformed 3 reacted with propanal. The structure assignment was corroborated by comparison with the 1D and 2D NMR spectra of an independently prepared sample (see Section 3).

S10
(E)-2-((2,2,5,5-Tetramethyl-1-styryl-2,5-dihydro-1H-imidazol-4-yl)thio)acetonitrile (5)    The crystal used for X-ray crystallographic data was prepared by the diffusion method where a sample of 5 was diluted in a vial with CH 2 Cl 2 and placed in a chamber of pentane filled with N 2 gas. The sample was left to sit in the fridge (7 °C) undisturbed for 4 days. The crystal was isolated as a yellow needle and characterised by X-ray crystallography (Section 4).

Crystallographic data for enamine 5
The X-ray intensity data of 5 (av098) were measured on a Bruker D8 Venture TXS system equipped with a multilayer mirror monochromator and a Mo Kα rotating anode X-ray tube (λ = 0.71073 Å). The frames were integrated with the Bruker SAINT software package. S5 Data were corrected for absorption effects using the Multi-Scan method (SADABS). S6 The structure was solved and refined using the Bruker SHELXTL Software Package. S7 All hydrogen atoms were calculated in ideal geometry riding on their parent atoms.
To a solution of 7d (
To a solution of 7e (82.2 mg, 0.209 mmol) in acetonitrile (4.1 mL) was added 4 (56.3 mg, 0.237 mmol) in acetonitrile (4.1 mL) in one portion at room temperature, at which point the reaction mixture changed colour from blue to brown. After 40 min, to the solution was added 2 M aq HCl (3 mL). This mixture was left to stir at room temperature for 30 min.
Subsequently, the solution was mixed with CH 2 Cl 2 (10 mL) and then washed with aq saturated NaHCO 3 solution. The organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were dried over MgSO 4 , and the volatiles were evaporated under vacuum. The crude product was purified by flash chromatography (silica gel, loaded with CH 2 Cl 2 , eluent: pentane/EtOAc 9:1) to give 9b (
To a solution of 7g (80.3 mg, 0.220 mmol) in acetonitrile (2.4 mL) was added 4 (99.7 mg, 0.420 mmol) in acetonitrile (2.2 mL) in one portion at room temperature, at which point the reaction mixture changed colour from blue to green. After 1 h, to the solution was added 2 M aq HCl (3 mL). This mixture was left to stir at room temperature for 30 min. Subsequently, the solution was mixed with CH 2 Cl 2 (10 mL) and then washed with aq saturated NaHCO 3 solution. The organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were dried over MgSO 4 , and the volatiles were evaporated under vacuum. The crude product was purified by flash chromatography (silica gel, CH 2 Cl 2 /Et 2 O 6:1) to furnish 9c (54.6 mg, yield: 74%) as a colorless oil; R f = 0.50 (silica gel, CH 2 Cl 2 /Et 2 O 4:1).
To the mixture in the NMR tube was added bromoacetonitrile (98.1 mg, 0.818 mmol) and CD 3 CN. The NMR cap was added, and the tube was removed from the glovebox. The pale-yellow solution in the NMR tube was irradiated with a Roithner LaserTechnik-H2A1-H365 emitter (365 nm) for 1 h. During this time, the solution turned to a bright yellow colour. NMR spectroscopy indicated that enamine 4 was consumed completely and enamine 6 was formed. This solution was used without further purification to characterise 6 by NMR spectroscopy. Additional resonances in the NMR spectra were assigned to 2,6-lutidine, the secondary amine 3, and bromoacetonitrile: S18 To the mixture in the NMR tube was added bromoacetonitrile (102 mg, 0.850 mmol), mesitylene (10.6 mg, 0.0882 mmol), and CD 3 CN.

H NMR (CD
The NMR cap was added, and the tube was removed from the glovebox. The NMR tube was wrapped in aluminium foil and heated in an oil bath at 40 °C. The foil was only removed from the NMR tube when traveling to and from the NMR spectrometer. The reaction was monitored by NMR spectroscopy over the course of 23 h. Table S2. Decrease in enamine 4 concentration and concurrent increase in the α-branched enamine 6 concentration over time (CD 3 CN, 40 °C, dark, full spectra are shown in Figure S2) as exemplified by the change of the resonances for 10-H and 11-H of 6 and 10-H of 4. Concentrations of enamines 4 and 6 were calculated based on the integration of the mesitylene internal standard at δ 6.77 ppm (10.6 mg, 0.0882 mmol).

Spectra t (min)
Integration mesitylene (δ 6.77, 3H) Integration 4 (δ 1.63, 3 H, 10-H) Integration 6 (δ 1.82, 3 H, 10-H) 4 (mmol) 6 (mmol) 1.00 0.04 a 0.52 0.0106 a 0.0467 a As minor side products were present at the location of the 10-H resonance of enamine 4 (δ 1.63 ppm) after 23 hours, the concentration of enamine 4 at t = 1385 min was calculated based on the 8-H peak for enamine 4 (δ 5.93 ppm, 1 H). To an NMR tube was added propanal (80 µL, 1.12 mmol), bromoacetonitrile (26.6 mg, 0.222 mmol), 2,4,6-collidine (59 µL, 0.446 mmol), and the secondary amine TIM 3 (8.6 mg, 0.044 mmol) in CD 3 CN (0.5 mL). The solution was slightly yellow and clear. The tube was then irradiated with a Roithner LaserTechnik-H2A1-H365 emitter (365 nm) placed below for 17 h. At this point large crystalline white solids accumulated in the NMR tube, but the solution remained slightly yellow. To the solution was added additional CD 3 CN (approximately 0.5 mL, the white solids did not dissolve) and then an 1 H NMR spectrum was recorded to confirm the consumption of bromoacetonitrile (MJH-III-153.1). To the NMR tube was added mesitylene (13.8 mg, 0.115 mmol) as an internal integration standard, and the yield of 2 was determined to be 82%. NMR spectroscopic data for 2 agree with those reported previously. S10   To an NMR tube was added propanal (80 µL, 1.12 mmol), bromoacetonitrile (26.7 mg, 0.223 mmol), 2,4,6-collidine (59 µL, 0.446 mmol), and the secondary amine TIM 3 (8.6 mg, 0.044 mmol) in CD 3 CN (0.5 mL). The solution was slightly yellow and clear. The NMR tube was stored at ambient temperature in a black paper bag (to keep it in the dark). After a reaction time of 22.5 h, mesitylene (6.9 mg, 0.058 mmol) was added as an internal integration standard to the NMR sample. The yield of 2 was determined to be 6 %. NMR spectroscopic data for 2 agree with those reported in Section 9.

(TIM 3)-catalysed reaction (in the dark)
About 60% of the initial amount of the free catalyst TIM 3 (0.027 mmol) was still detectable in the NMR sample. The remaining 40% of the initially added cyclic amine 3 reacted with propanal to furnish enamine 4 (0.017 mmol). Only trace amounts (< 1%) of enamine 6 were detected.
Further resonances in the mixture were assigned to remaining starting materials.  The content of 4 in a mixture containing 2,6-lutidine, 3, 4, and acetonitrile (total: 165.4 mg) was determined to be 23.7 mg (see Figure S3 for the 1 H NMR spectrum of the sample). This mass was used to calculate the concentrations of the enamine 4. k 2 = 2.14 × 10 1 M −1 s −1 a The content of 4 in a mixture containing 2,6-lutidine, 3, 4, and acetonitrile (total: 165.4 mg) was determined to be 23.7 mg (see Figure S3 for the 1 H NMR spectrum of the sample). This mass was used to calculate the concentrations of the enamine 4.   Figure S3 for the 1 H NMR spectrum of the sample). This mass was used to calculate the concentrations of the enamine 4. The content of 4 in a mixture containing 2,6-lutidine, 3, 4, and acetonitrile (total: 226.3 mg) was determined to be 57.9 mg (see Figure S4 for the 1 H NMR spectrum of the sample). This mass was used to calculate the concentrations of the enamine 4.           Table S14. Second-order rate constants k 2 for the reactions of the enamine 5 with benzhydrylium tetrafluoroborates 7 (CH 2 Cl 2 , 20 °C) and determination of the reactivity parameters N (and s N ) for 5 in dichloromethane.